In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropicxe2x80x9d. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular Pharmacology 44: 505-510, 1993. It is not yet known how these sub-units are combined in the natural state. However, the structures of certain human variants of each sub-unit have been elucidated, and cell lines expressing individual sub-unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulate their function. Thus, European patent application, publication number EP-A2-0574257 discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B. European patent application, publication number EP-A1-0583917 discloses the human sub-unit variant GluR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid deactivation and desensitization to glutamate. Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647.
It is known that the rapid desensitization and deactivation of AMPA and/or kainic acid receptors to glutamate may be inhibited using certain compounds. This action of these compounds is often referred to in the alternative as xe2x80x9cpotentiationxe2x80x9d of the receptors. One such compound, which selectively potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron. Vol. 11, 1069-1082, 1993.
International Patent Application Publication WO 98/33496 published Aug. 6, 1998 discloses certain sulfonamide derivatives which are useful, for example, for treating psychiatric and neurological disorders, for example cognitive disorders; neuro-degenerative disorders such as Alzheimer""s disease; age-related dementias; age-induced memory impairment; movement disorders such as tardive dyskinesia, Huntington""s chorea, myoclonus, and Parkinson""s disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder, psychosis; cognitive deficits associated with psychosis, and drug-induced psychosis.
The present invention provides compounds of formula I: 
or a pharmaceutically acceptable salt thereof.
The present invention further provides a compound of formula Ia: 
or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of potentiating glutamate receptor function in a patient which comprises administering to said patient an effective amount of a compound of formula Ia.
In addition, the present invention provides a method of treating depression in a patient comprising administering to said patient an effective amount of a compound of formula Ia.
The present invention further provides a method of treating schizophrenia in a patient comprising administering to said patient an effective amount of a compound of formula Ia.
Furthermore, the present invention provides a method of treating cognitive disorders in a patient comprising administering to said patient an effective amount of a compound of formula Ia.
The invention further provides pharmaceutical compositions of compounds of formula Ia, including the hydrates thereof, comprising, as an active ingredient, a compound of formula Ia in combination with a pharmaceutically acceptable carrier, diluent or excipient.
This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula Ia.
In addition, the present invention provides the use of a compound of formula Ia or a pharmaceutically acceptable salt thereof for potentiating glutamate receptor function.
According to another aspect, the present invention provides the use of a compound of formula Ia for the manufacture of a medicament for potentiating glutamate receptor function.
The present invention further provides an article of manufacture comprising packaging material and a compound of formula Ia or a pharmaceutically acceptable salt thereof contained within said packaging material, wherein said packaging material comprises a label which indicates that said compound of formula Ia can be used for treating at least one of the following; Alzheimer""s disease, schizophrenia, cognitive deficits associated with schizophrenia, depression, and cognitive disorders.